One of the major goals of the field of human genetics is to define the relationship between human genotype and phenotype. Much of our assessment of genotypic variation has been focused on small scale, single nucleotide events. Our understanding of the molecular basis of disease, however, has begun to reveal that large-scale differences including micro duplications and micro deletions contribute significantly to childhood disease, disease susceptibility and normal variation in the population. Despite its importance, there has been no systematic study of this form of genotypic variation. The long-term objective of this proposal is to investigate the pattern and nature of this large-scale variation. Our approach will be directed to regions of the genome that contain highly homologous duplicated sequence and therefore have an increased probability of genomic gain and loss. This proposal is a collaborative effort that brings together expertise in genome structure, array comparative genomic hybridization technology and mental retardation. The specific aims of this proposal are (1) to identify and validate all intrachromosomally duplicated regions within the human genome, (2) to develop a set of large-insert clones bracketed by duplicated sequence to be placed on a CGH microarray platform for genome-wide screening, (3) to assess copy number variation within both normal individuals and children with idiopathic mental retardation and (4) to validate the extent, frequency and inheritance pattern of these large structural "polymorphisms". This project aims to address two fundamental questions; what is the nature and frequency of duplication-mediated structural polymorphisms within the human genome? Are there an excess of de novo events among children with mental retardation and congenital birth defects?